My lab previously identified H3K4 methyltransferases MLL3 and MLL4 (Cho YW, JBC 2007) and H3K27 demethylases UTX and JMJD3 (Hong S, PNAS 2007). Using a nuclear protein PTIP as the bait, we isolated from cell nuclei a protein complex that contains H3K4 methyltransferases MLL3/MLL4, H3K27 demethylase UTX, PTIP and a novel protein PA1 (Cho YW, JBC 2007). Further, we show that PTIP is required for PPARgamma and C/EBPalpha expression and adipogenesis (Cho, YW, Cell Metab 2009). To understand the physiological roles of MLL3/MLL4 and associated factors, we have knocked out MLL3, MLL4, UTX and PA1 in mice. Because of their embryonic lethality, we have generated conditional knockout (KO) of MLL4, UTX and PA1. We also generated enzyme-dead UTX knockin mice (Faralli H, JCI 2016). We found that UTX protein, but not its H3K27 demethylase activity, is required for embryonic stem cell differentiation, establishment of the mammary luminal cell lineage, and mouse development (Wang C, PNAS 2012; Yoo KH, MCB 2016; Faralli H, JCI 2016). Our data suggest that UTX functions through MLL3/MLL4 to regulate enhancer activation during cell differentiation and animal development. Interestingly, UTX demethylase activity is required for satellite cell-mediated muscle regeneration (Faralli H, JCI 2016). Using adipogenesis and myogenesis and embryonic stem cell differentiation as model systems, we found that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL3 and MLL4 are redundant and are essential for enhancer activation, cell-type-specific gene expression and cell differentiation (Lee J, eLife, 2013; Wang C, unpublished). MLL4 is also required for heart development (Ang SY, Development 2016). MLL3/MLL4 and UTX are frequently mutated in multiple types of cancers and developmental diseases. Our findings suggest that mutations in MLL3/MLL4 and UTX would lead to defects in enhancer activation, cell-type-specific gene expression and cell differentiation. Such a mechanism may contribute to the pathogenesis of these cancers and developmental diseases.